1. Normal Pubertal Development: Part I: The Endocrine Basis of Puberty
Brian Bordini and Robert L. Rosenfield
Pediatr. Rev. 2011;32;223-229
DOI: 10.1542/pir.32-6-223
The online version of this article, along with updated information and services, is
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2. Article adolescent medicine
Normal Pubertal Development:
Part I: The Endocrine Basis of Puberty
Brian Bordini, MD,*
Objectives After completing this article, readers should be able to:
Robert L. Rosenfield, MD*
1. Explain how puberty is regulated by the hypothalamic-pituitary-gonadal axis.
2. Describe the hormonal interactions involved in pubertal development in boys and girls.
Author Disclosure
Drs Bordini and Introduction
Rosenfield have Puberty is a defining developmental stage of every child’s life, both physically and
disclosed no financial psychosocially. Concerns about the normalcy of pubertal development and menstrual
relationships relevant patterns are among the most common questions posed to every physician caring for
to this article. This children. This article reviews the primary physiologic changes in the hypothalamic-
pituitary-gonadal (HPG) axis and in adrenal androgen and growth hormone (GH)
commentary does not
production that underlie the normal pubertal milestones. Understanding of these changes
contain a discussion allows interpretation of laboratory data in children suspected of having pubertal abnor-
of an unapproved/ malities.
investigative use of a Puberty is the developmental stage during which a child becomes a young adult,
commercial product/ characterized by the maturation of gametogenesis, secretion of gonadal hormones, and
device. development of secondary sexual characteristics and reproductive functions. Adolescence is
used widely as a generally synonymous term for puberty, but the term often is used to
convey an added connotation of cognitive, psychological, and social change.
Thelarche denotes the onset of breast development, an estrogen effect. Pubarche
denotes the onset of sexual hair growth, an androgen effect. Menarche indicates the onset
of menses and spermarche the appearance of spermatozoa in seminal fluid. Gonadarche
refers to the onset of pubertal function of the gonads, which produce most of the sex
hormones that underlie the pubertal changes in secondary sex characteristics. Adrenarche
refers to the onset of the adrenal androgen production that contributes to pubarche.
The Hormonal Axes Underlying Puberty
The Hypothalamic-Pituitary-Gonadal Axis
Normal puberty results from sustained, mature activity of the HPG axis. (1). The major
hormones of the HPG axis are shown in Figure 1. In response to a single gonadotropin-
releasing hormone (GnRH), the pituitary gland releases two gonadotropins: luteinizing
hormone (LH) and follicle-stimulating hormone (FSH). GnRH is secreted by specialized
neurons of the hypothalamus in a pulsatile fashion. Pituitary LH and FSH secretion
consequently is pulsatile and can be sustained only in response to pulsatile GnRH signals.
LH acts primarily on the specialized interstitial cells of the gonads to stimulate formation
of androgens, and FSH acts primarily on the follicular/tubular compartment to stimulate
formation of estrogen from androgen precursors, inhibin,
and gametes. The function of the two compartments of the
gonads is coordinated by paracrine regulatory mechanisms.
Abbreviations The HPG axis is active during three phases of develop-
ACTH: adrenocorticotropic hormone ment: fetal, neonatal, and adult, with puberty being the
DHEAS: dehydroepiandrosterone sulfate period of transition to mature function. Changes in GnRH
FSH: follicle-stimulating hormone secretion underlie the changing activity of the HPG axis. The
GH: growth hormone sexually dimorphic patterns of sex hormone secretion during
GnRH: gonadotropin-releasing hormone the prenatal and neonatal periods of HPG activity appear to
HPG: hypothalamic-pituitary-gonadal play a role in programming sexually dimorphic patterns of
LH: luteinizing hormone behavior, metabolism, and neuroendocrine function in later
life.
*Section of Adult and Pediatric Endocrinology, The University of Chicago Pritzker School of Medicine, Chicago, IL.
Pediatrics in Review Vol.32 No.6 June 2011 223

3. adolescent medicine pubertal development
ingly active again in the late prepubertal period, as central
nervous system restraint recedes, followed by an increas-
ing tempo throughout puberty.
The gonads account for the most important circulat-
ing estrogen (estradiol) and androgen (testosterone).
Gonadal function accounts for more than 90% of estra-
diol production in the female (50% in the male) and more
than 90% of testosterone production in the male (50% in
the female) (Fig. 2). (4)(5)
Figure 1. The hypothalamic-pituitary-gonadal axis. Hypo-
thalamic neurons release gonadotropin-releasing hormone
(GnRH) into the pituitary portal venous system, where it stimu-
lates gonadotropin (luteinizing hormone [LH] and follicle-
stimulating hormone [FSH]) secretion. LH primarily stimulates
specialized interstitial cells (theca cells in the ovary or Leydig cells
in the testes) to secrete androgens. FSH primarily stimulates the
ovarian follicle or seminiferous tubules to form estrogen, inhibin,
and gametes (eggs or sperm). The interstitial and follicular/
tubular compartments act cooperatively through paracrine
mechanisms to form estrogen and to regulate sex steroid and
gamete development. Sex steroids exert endocrine closed-loop
negative feedback effects on GnRH and gonadotropin secretion.
Inhibin exerts negative feedback on FSH secretion. In mature
females, a critical estradiol concentration for a critical duration
exerts a transient positive feedback effect to stimulate the LH
surge that initiates ovulation.
The HPG axis is established during the first trimester.
Its activity in the second trimester contributes to the
establishment of normal penile size and the inguinal-
scrotal phase of testicular descent. (2)(3) In the latter half Figure 2. Simplified diagram of sex steroid production by
of pregnancy, activity is suppressed by the high estrogens the adult adrenal glands, follicular phase ovaries, and testes.
elaborated by the fetoplacental unit. Blood production rates shown are the sum of direct secretion
The HPG axis promptly functions at a pubertal level (heavy solid arrows) and peripheral formation from secreted
in the newborn after withdrawal from maternal estro- precursors (dotted arrows). Several key steroidogenic enzyme
gens. This “minipuberty of the newborn” is subclinical, activities expressed in these glands, such as sulfotransferase
except for contributing to genital growth, acne, and (SULT), 3 -hydroxysteroid dehydrogenase (3 ), aromatase,
transient thelarche in the neonate. and 17 -hydroxysteroid dehydrogenase type 5 (17 HSD5),
are also expressed in peripheral tissues such as liver, fat, and
HPG function subsequently comes under gradual
skin. Type 3 17 HSD (17 HSD3) is only expressed in testes.
central nervous system restraint at the end of the neo-
Peripheral conversion from secreted androstenedione accounts
natal period. The axis is relatively, but not absolutely, for 50% of testosterone in women, and about 10% of estra-
dormant throughout childhood, particularly in girls, diol and DHEAS similarly arise from circulating precursors.
who have slightly higher FSH concentrations than boys Estrone, the intermediate in the pathway from androstenedione to
and a few ultrasonographically visible ovarian follicles as estradiol, is not shown. DHEA dehydroepiandrosterone, DHEAS
evidence of this effect. The HPG axis becomes increas- dehydroepiandrosterone sulfate, A’DIONE androstenedione
224 Pediatrics in Review Vol.32 No.6 June 2011

4. adolescent medicine pubertal development
Adrenarche, the “Puberty” of the insulin-like growth factor-I concentrations to peaks in
Adrenal Gland late puberty that are above those of adults, sometimes in
Adrenarche is actually a re-onset of adrenal androgen the adult acromegalic range. Half of the characteristic
production. The fetal zone of the adrenal cortex elabo- pubertal growth spurt is due to the direct effect of sex
rates large amounts of dehydroepiandrosterone sulfate steroids on epiphyseal growth and half to GH stimula-
(DHEAS), which is important as the major substrate for tion. Conversely, in accord with the general principle
placental estrogen formation during pregnancy. This that everything grows better with GH, GH is necessary
zone then regresses over the first several postnatal for optimal gonadotropin effects on gonadal growth and
months. sex steroid effects on secondary sex characteristics. For
Adrenarche is the pseudopuberty of the adrenal gland example, selective GH resistance is characterized by small
that begins in mid-childhood as the zona reticularis of testes and micropenis, poor breast and sexual hair devel-
the adrenal cortex develops. (1) This zone has the capac- opment, and absence of a pubertal growth spurt. (12)
ity to form 17-ketosteroids, but not cortisol, in response
to adrenocorticotropic hormone (ACTH), and DHEAS Regulation of the Onset and Progression
is the primary endpoint of this biosynthetic pathway. of Puberty
Consequently, although cortisol concentrations and the There is no single “trigger” for puberty; rather, puberty
cortisol response to ACTH do not change from child- results from a gradual increase in GnRH pulsatility that
hood to adulthood, DHEAS values gradually rise from arises from maturation of central nervous system devel-
mid-childhood until adulthood. This timeframe coin- opmental programs that send inhibitory and stimulatory
cides approximately with the gonadal androgen produc- signals to GnRH neurons. (1) Puberty is associated with
tion of true puberty, but adrenarche is an incomplete changing sensitivity of the neuroendocrine system to
aspect of puberty that is independent of pubertal matu- negative feedback by gonadal hormones. When GnRH
ration of the HPG axis. The adrenal gland secretes more secretory activity is low due to central nervous system
than 90% of DHEAS in children and women and more inhibition in mid-childhood, it is inhibited by trace
than 70% in adult men, while 50% of testosterone in the amounts of sex steroids. Increasing central activation
female and less than 10% of testosterone in the male is during puberty permits sex steroids to rise to adult con-
produced by the adrenal. (6) Adrenal androgen concen- centrations before exerting negative feedback effects.
trations increase to a point sufficient to stimulate apo- The major GnRH-inhibitory systems are GABAergic
crine odor and mild acne after about 5 years of age and and opioidergic; the major excitatory systems involve
pubic hair growth after about 10 years of age (Table). glutamate and kisspeptin, with glial cells facilitating
GnRH secretion. Kisspeptin is a hypothalamic neuro-
Interactions Between Pubertal Hormones and peptide discovered in the search for the molecular basis
the Growth Hormone/Insulin-like Growth of hypogonadotropic hypogonadism; it acts as an im-
Factor-I Axis portant signal for pubertal GnRH release via GPR54, a
Pituitary GH secretion increases during puberty in re- G-protein coupled receptor located on GnRH neurons.
sponse to sex steroids. (1) This rise in GH causes a rise in It has been estimated that at least half of the varia-
Table. Typical Early Morning Pubertal Hormone Blood Concentrations
LH FSH Estradiol TT DHEAS
Group (IU/L) (IU/L) (pg/mL) (ng/dL) ( g/dL)
Prepubertal 1 to 5 yr <0.3 <4.0 <10 <20 5 to 40*
Premenarchal females <12 1.0 to 12 <50 13 to 44 35 to 130
Postmenarchal females** 2.0 to 11 1.0 to 12 20 to 85 15 to 59 75 to 255
Adult men*** 1.4 to 9.0 1.0 to 9.2 <60 300 to 950 100 to 460
DHEAS dehydroepiandrosterone sulfate, FSH follicle-stimulating hormone, LH luteinizing hormone, TT total testosterone
Conversions to SI units: estradiol 3.61 pmol/L, testosterone 0.0347 nmol/L, DHEAS 0.0271 mol/L
Assay-specific ranges may vary.
*Prepubertal children 6 to 9 years of age may have adrenarchal DHEAS values up to approximately 70 g/dL
**Early follicular phase values given; mid-cycle LH up to 85 IU/L, FSH up to 19 U/L, estradiol up to 350 pg/mL
***Pubertal males values are between and overlap with prepubertal and adult male values
Data from Bordini et al, (7) Mortensen et al, (8) Zimmer et al, (9) Mayo Clinical Laboratories, (10) Esoterix Laboratory Services. (11)
Pediatrics in Review Vol.32 No.6 June 2011 225

5. adolescent medicine pubertal development
tion in the timing of puberty is genetically determined, pulsatile secretion during sleep (Fig. 3). (18)(19) In
and ethnicity is one such factor. (1)(13) Sex hormones, response to nocturnal LH secretion, the pattern of go-
hormonally active environmental chemicals (“environmen- nadal sex steroid secretion differs between the sexes:
tal disruptors”), (14) diverse somatic stimuli (including ovarian secretion of estradiol peaks in mid-day and tes-
nutrition, the growth hormone/insulin-like growth factor ticular secretion of testosterone peaks promptly during
system, thyroid hormones), and general health all affect the sleep. In addition, girls’ pubertal hormone secretion is
pubertal process. subclinically cyclic from early puberty. As puberty pro-
Pubertal and skeletal maturation appear to have com- gresses, LH secretion persists further into the daytime.
mon somatic determinants. Children generally enter pu- After menarche, this diurnal variation no longer exists.
berty when they achieve a pubertal bone age. Pubertal Adult sex steroid concentrations, however, have a mild
stage normally correlates better with the bone age than diurnal variation, being highest on awakening.
with chronologic age. (15) Thus, for example, the onset The two gonadotropins each act primarily on specific
of breast development normally occurs at a bone age of gonadal cell types. LH stimulates the interstitial cells of
about 10 years and menarche occurs at a bone age of about the ovaries (theca cells) to form androgenic precursors of
12.5 years, whether the child is 9 or 14 years of age. estradiol and those of the testes (Leydig cells) to secrete
Optimal nutrition is necessary for initiation and main- testosterone itself. FSH acts on the sex cord derivatives of
tenance of normal reproductive function. The hypothesis the ovary (granulosa cells) and testes (Sertoli cells) to
that a critical amount of body fat is the weight-related stimulate gametogenesis and gonadal growth. In granu-
trigger for pubertal development originated with the dis- losa cells, FSH strongly stimulates aromatase to form
covery by Frisch and coworkers that weight correlated with estradiol from thecal androgens.
pubertal growth and menarche better than it did with As the gonads become increasingly sensitized to
chronologic age or height. (16) Early to mid-childhood gonadotropin stimulation, they grow and secrete sex
may be a critical period for weight to influence the onset of hormones at steadily increased rates. Within 3 years of
puberty. (17) Suboptimal nutrition related to socioeco- rising above the prepubertal range, estradiol increases an
nomic conditions is an important factor in the late onset of average of 20 pg/mL (73.4 pmol/L) yearly to reach the
puberty in underdeveloped countries. Conversely, obesity is mid-adult range and testosterone increases an average of
an important factor in advancing the onset of puberty in 100 ng/dL (3.47 nmol/L) yearly to reach the lower
United States girls. (13) adult range (Table). (20) These concentrations then
Leptin, a hormone secreted by fat cells, appears to be gradually induce their effects. The hormonal increases
an important link between nutrition and the attainment culminate in positive feedback in girls, which refers to the
and maintenance of reproductive competence. (1) Lep- female neuroendocrine system becoming capable of se-
tin acts on the hypothalamus to reduce appetite and creting a mid-cycle surge of LH when the ovary signals
stimulate gonadotropin secretion. Leptin deficiency that it is prepared for ovulation via a critical and sustained
causes obesity and gonadotropin deficiency. Blood leptin level of estrogen secretion.
concentrations rise throughout childhood and puberty Estrogen stimulates the classic female target tissues:
to reach higher values in girls than boys. Attainment of a the female genital tract (eg, endometrial growth, cervical
critical threshold appears to signal that nutritional stores mucus secretion) and breasts. Androgen stimulates the
are sufficient for mature function of the GnRH pulse classic male target tissues (eg, sexual hair and sebaceous
generator and, thus, permits puberty. gland). Both stimulate sexual drive and function. Both
Although prolactin and pineal gland hormones affect sex steroids account for the pubertal growth spurt, di-
puberty in lower animals and can cause pubertal disor- rectly and indirectly via growth hormone. Both directly
ders in humans, neither has a clear role in normal human stimulate epiphyseal growth and epiphyseal maturation,
puberty. which is indexed by bone age radiographs and peak bone
mass accrual. (21) However, they differ in some of their
Hormonal Changes of Normal Puberty effects on skeletal growth. Androgen is responsible for
The first hormonal change of puberty is a sleep-related the wider bones (the laryngeal enlargement accounting
increase in the pulsatile release of LH by the pituitary for the pubertal voice change), while estrogen is ulti-
gonadotropes. FSH is secreted in parallel but increases mately necessary for epiphyseal fusion and is the more
relatively less. At the beginning of puberty, a unique potent inhibitor of bone resorption. They also affect
diurnal variation of pubertal hormones occurs, with little growth of a wide variety of other somatic tissues. During
LH secretion during the day and a significant increase in puberty, estrogen promotes lipogenesis and lower body
226 Pediatrics in Review Vol.32 No.6 June 2011

6. adolescent medicine pubertal development
Figure 4. Diagram of average gonadotropin and sex steroid
concentrations during the normal menstrual cycle. The data
are centered in reference to days before ( ) or after ( ) the
day of the mid-cycle surge of luteinizing hormone (LH). The
gonadotropin concentrations are typical of polyclonal radio-
immunoassay, and the baseline values are about twice as high
as those obtained by current monoclonal assays. M menses
begin, E2 estradiol, PROG progesterone. Reprinted with
permission from Rosenfield et al. (1)
fat distribution. In contrast, androgens generally are
lipolytic, although they favor the development of visceral
fat stores, and promote muscular development. The sim-
ilar increase of body mass index during puberty in girls
Figure 3. Pubertal hormone rhythms. In an early pubertal girl and boys, thus, is due to differences in body composition,
(top panel), luteinizing hormone (LH) secretion is minimal with a higher percent being body fat in girls and lean
during waking hours. Pubertal LH pulsations promptly begin body mass in boys. (22)
with sleep onset and wane with sleep offset, followed several The menstrual cycle arises from cyclic maturation of
hours later by increased ovarian estradiol secretion that peaks ovarian follicles that result in cyclic changes in sex hor-
mid-day. Reprinted with permission from Boyar et al. (18) mones, particularly estradiol and progesterone, which
Copyright 1976, The Endocrine Society. In an early pubertal
entrain cyclic changes in gonadotropin concentrations
boy (bottom panel), daytime LH values are low, with minimal
(Fig. 4). The biologic goal of this monthly variation is to
testosterone secretion. Pubertal LH pulsations begin promptly
with sleep onset and cease with sleep offset; testosterone select and nurture one dominant follicle to the point of
secretion occurs primarily during sleep, beginning about ovulation for potential fertilization. A normal average
2 hours after LH increases and waning on awakening. Re- 28-day cycle consists of two phases: the follicular phase
printed with permission from Judd et al. (19) Copyright 1974, (variable in duration, averaging 14 days at maturity) and
The Endocrine Society. Panels are modified by aligning times. the luteal phase (14 1 SD days), with the latter occur-
This figure demonstrates the clinical importance of consider- ring only in ovulatory cycles. The follicular phase begins
ing diurnal and pulsatile hormone secretion in evaluating with the onset of menses and culminates in the mid-cycle
pubertal status. First, because of diurnal rhythmicity, daytime LH surge, which induces ovulation from the follicle. The
hormone values during early puberty are not representative empty follicle forms the corpus luteum, initiating the
of the 24-hour production of pubertal hormones, as indicated
luteal phase. Progesterone increases steadily to be sus-
for LH in this girl (breast stage 3) and for testosterone and
tained at very high levels for several days, along with
gonadotropins in this boy (stage 2). Second, because of the
episodic pulsatile nature of gonadotropin and sex steroid lesser but substantial increases in estradiol. Progesterone
secretion, hormone values may differ markedly within 1 hour. and estradiol secretion from the corpus luteum maintain
The gonadotropin concentrations were determined by early- the endometrial layer of the uterus in preparation for
generation radioimmunoassays, and the baseline values are potential pregnancy. If pregnancy does not occur, with
higher than those obtained by current assays. its resultant increase in human chorionic gonadotropin,
Pediatrics in Review Vol.32 No.6 June 2011 227

7. adolescent medicine pubertal development
the corpus luteum life span is exhausted, which results References
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Philadelphia, PA: Elsevier; 2008:530 – 609
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Accessed March 2011 at: www.mayomedicallaboratories.com
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PIR Quiz
Quiz questions also available online at http://pedsinreview.aappublications.org.
1. Which of the following statements about normal puberty in children is true?
A. Bone age correlates better with pubertal development than chronologic age.
B. Gonadotropin-releasing hormone (GnRH) secretion in response to negative feedback from sex steroids is
constant throughout life.
C. Growth hormone secretion is the sole determinant of the pubertal growth spurt.
D. Menarche is the first stage of puberty in girls.
E. Normal pubertal development is unrelated to nutritional status.
2. Which of the following statements best describes adrenarche?
A. Breast development becomes evident in girls.
B. Hypothalamic production of adrenocorticotropin hormone increases.
C. Maternal estrogens are withdrawn, causing neonatal acne.
D. Spermatozoa begin to appear in seminal fluid.
E. The adrenal gland increases production of dehydroepiandrosterone sulfate.
3. Which of the following is the primary action of luteinizing hormone?
A. Secretion of follicle-stimulating hormone.
B. Secretion of GnRH from the pituitary gland.
C. Stimulation of gametogenesis in the testes.
D. Stimulation of the gonads to produce androgens.
E. Stimulation of the ovarian follicle to produce estrogen.
4. At which of the following phases of the menstrual cycle is the concentration of progesterone the highest?
A. The beginning of the follicular phase.
B. The beginning of the luteal phase.
C. The end of the luteal phase.
D. The middle of the follicular phase.
E. The middle of the luteal phase.
HealthyChildren.org Parent Resources from AAP
The reader is likely to find material to share with parents that is relevant to this article by
visiting this link: http://www.healthychildren.org/English/ages-stages/gradeschool/
puberty/Pages/default.aspx.
Pediatrics in Review Vol.32 No.6 June 2011 229

9. Normal Pubertal Development: Part I: The Endocrine Basis of Puberty
Brian Bordini and Robert L. Rosenfield
Pediatr. Rev. 2011;32;223-229
DOI: 10.1542/pir.32-6-223
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_disorders
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